Hepatocyte growth factor (HGF) has anti-fibrogenic properties. However, several studies have shown that HGF only affects fibroblasts expressing the HGF receptor known as cellular mesenchymal-epithelial transition factor (c-MET, MET). During fibrotic diseases, such as scleroderma, pulmonary fibrosis and hepatic fibrosis, c-MET is found to be overexpressed and HGF to be at elevated concentrations compared to normal, indicating their function in a biological feedback process to deal with increasing collagen levels. However, the elevated levels are insufficient to regulate the fibrotic process.
Pulmonary fibrosis is the most severe complication and the leading cause of mortality in scleroderma. Although SSc-ILD is detected in more than 90% of patients (D'Angelo W A, et al., Am J Med., 1969, 46(3):428-40 and Steen V D, et al., Ann Rheum Dis., 2007, 66(7):940-4), disease progression is very heterogeneous, suggesting that SSc-ILD patients have some biological or genetic factors that differentially affect the pathogenic mechanisms of the disease. African American SSc patients exhibit higher prevalence of ILD and worse outcomes than those of other races (Nietert P J, et al., J Rheumatol, 2006, 33:263-268 and Silver R M, et al., Curr Opin Rheumatol., 2012, 24(6):642-8). It was previously reported that a cell-protective and anti-fibrotic agent, HGF, is downregulated in bronchoalveolar lavage fluid (BALF) and plasma from African American SSc-ILD patients compared with white SSc-ILD patients. Moreover, in SSc lung fibroblasts from white patients, HGF downregulates extracellular matrix proteins such as collagen and connective tissue growth factor (CTGF, CCN2), whereas in SSc fibroblasts from African Americans, HGF is not functional due to a deficiency in phosphorylation of the MET receptor (Bogatkevich G S, et al., Arthritis Rheum, 2007, 56:2432-42 and Bogatkevich G S, et al., Arthritis Rheum, 2007, 56:3468-77).
MET is a receptor tyrosine kinase implicated in embryonic development and tissue regeneration after acute injury (Ohmichi H, et al., Development, 1998, 125(7):1315-24 and Neuss S, et al., Stem Cells, 2004, 22:405-14). Following binding of HGF, MET undergoes auto phosphorylation at tyrosine residues in its cytoplasmic domain and initiates a cascade of signal transduction events leading to specific cellular responses (Stuart K A, et al., Int J Exp Pathol, 2000, 81:17-30 and Hammond D E, et al., Curr Top Microbiol Immunol, 2004, 286:21-44). Several studies have characterized the anti-fibrotic effects of MET on collagen, MMP-1, and CTGF in SSc skin fibroblasts (Jinnin M, et al., J Invest Dermatol, 2005, 124:324-30 and Sherriff-Tadano R, et al., Mod Rheumatol, 2006, 16:364-71).
The benefit of the overexpression of c-MET has been recognized in studies examining cardiac scarring, skin scleroderma, and hepatic fibrosis and has been proposed as a therapeutic approach. However, c-MET exhibits oncogenic properties which can be a problem.
Despite the advances made in the art for treatment of diseases and disorders involving the use of c-MET based therapy, there is a need in the art for improved compositions useful for the treatment of fibrotic diseases and disorders. The present invention fulfills these needs.